Injectable pharmaceutical solutions are unsuitable for use if particle contamination is visible in non-destructive visual inspection or the distribution of sub-visible particles exceed the number and distribution of the pharmacopeial quality standard in sampled destructive tests. Because of the nature of the use it is a requirement that, whenever possible, each container, having such solution, be subjected to visual quality control inspection and analysis to determine suitability. The pharmacopeial standard and basis for this test is that of a skilled human inspector, i.e. rejection on the basis of particles visible to the human eye. Human inspection is however costly, slow and variable, with efforts having been expended upon development of automated inspection systems.
For an automated particle contamination inspection system to be validated, its performance must be at least equivalent to that of the standard established by the skilled human inspector. In determining the basis for the skilled human standard, the range of inspected containers has been defined as encompassing three separate probability zones of container acceptability. Based upon the accepted quality definition, "bad" containers are those having a rejection probability equal to or greater than 70% in a single visual inspection (Reject Zone). "Good" containers are those rejected less than 30% in a single visual inspection (Accept Zone). Those containers having probabilities of rejection between 70 and 30% are categorized as being in a Gray Zone. Automated non-destructive inspection devices should provide an average rejection rate for all the containers, that human inspection identifies as being within the Reject Zone, and are matched by the device, within an acceptable confidence interval. In addition, for economic considerations, false rejection of Accept and Gray Zone containers should be minimal.
In real size terms, 100 .mu.m particles are the smallest that can be detected by experienced inspectors, with unaided vision, 70% of the time; 50 .mu.m particles are rarely detected; and 200 .mu.m particles are always detected. As a result, automated inspection should be able to reliably, (i.e. with probability of rejection equal to or greater than 70%) reject particles of 100 .mu.m and greater.
The evaluation of injectable products by visual inspection, where possible, and the determination that injectable products are "essentially free from particles that can be observed by visual inspection", mandate the visual or visual equivalent inspection as a prerequisite for product acceptance and sale.
At present, there is no automated inspection which delivers the required skilled human standard for inspection security and an acceptable false rejection rate in a single inspection. In order to achieve automated inspections comparable to those of human inspectors (without excessive rejections), it has therefore generally been necessary that containers be subjected to two or even three separate inspections. One common type of inspection is the "accept in two" strategy in which the containers accepted as good in the first inspection are sent to stock. The bad containers from a first inspection are re-inspected and if containers are then found to be good they are added to the accepted stock. An "accept in three" strategy adds a third inspection for the culling of additional acceptable stock, though with a reduction in security. A current widespread inspection strategy, used by Japanese and Italian inspection systems, involves a "reject in two" strategy in which a container is rejected if it fails to pass either of two serial inspections. The ability of a system to reject containers within the Reject Zone is defined as the Reject Zone Efficiency or RZE. Manual inspection peaks at about 90% RZE for a first inspection, with a slide to about 80% with a second ("accept in two") procedure. Reject Zone Efficiency, after the second inspection, must be matched for validation. RZE for a "reject in two" inspection usually ranges from 70-80%
In addition to the visual inspection, a destructive sampling procedure, for sub-visual particles, i.e., less than 50 .mu., is also employed for the evaluation of contaminating particles in these solutions. Marketed injectable solutions in the U.S.A. must contain fewer contaminating particles &gt;10 .mu.m and &gt;25 .mu.m than limits established by the U.S. Pharmacopoeia.
A commonly utilized form of automated non-destructive type of inspection, particularly in a sterile production line setting, involves the illumination of suspended particles, with detection of the particle images for a determination of particle size and number. Various procedures have evolved to minimize either uneconomical excessive rejection rates of potentially acceptable containers or undesired acceptance of rejectable containers with consequent degradation in quality. Nevertheless, a high degree of inaccuracy remains, with acceptance of containers which should be rejected and rejection of containers which should be accepted.
A common automated procedure, exemplified by U.S. Pat. Nos. 3,627,423 and 4,676,650; for non-destructive inspection, entails rapid rotation of the solution container about its own axis, with the container being suddenly stopped. Because of inertia, particles within the solution, continue in motion, in generally decaying circular spirals. The orbits and decay times are related to the size, weight and hydrodynamic characteristics of the individual particles and to the viscosity of the suspending solution. The moving particles are then illuminated for inspection and the image signals of the illuminated particle are detected and evaluated for size and number. The particle movement and illumination thereof enables the ready differentiation of the moving particles from static imperfections in the container material, usually of a non-optical grade of glass, from external dirt particles on the container, or printed information thereon. Another method for inducing particle movement or motion is inversion of the container during illumination and inspection. The post spin or inversion inspection can be accomplished with either a stationary container or one in continuous rotational translation, i.e., moving an assembly within a turret.
Errors are, however, inherent in the present common scanning methods which make it difficult to achieve more than about 80% rejectable container rejections, with the "reject in two" inspection, and 90% rejectable container rejections, with the "accept in three" inspections. Several major factors in prior art methods result in limitations of accuracy. In these methods, only a fraction of the particles in the container volume are effectively illuminated and imaged during a single inspection. The position of the particle at commencement of the inspection is random. To be detected, the particle must traverse the limited inspected volume. This required condition results from particle illumination and/or imaging being limited to particles in a small portion of the container volume. For the "reject in two" automated inspection, the inspected volume can be a rectangular volume approximately 1 mm thick, centered on the optical axis of the inspection system. For particle imaging systems, the shallow-depth inspected volume, using this inspection strategy, is centered generally on the optical axis of the container near the container wall. The signals from these particles are considered an optical signature which is compared to stored criteria to determine particle contamination of the entire solution.
The security of the inspection, however, can be no better than the proportion of the total container liquid volume examined in the inspection. It is therefore essential that substantially all of the container liquid volume be examined for particles. In the present art, the use of separate inspections does not effect this desirable full container inspection, due to the random portion of the particles at the start of each inspection. Instead it provides an improvement in probabilistic detection capability. However, the use of multiple inspections, with container rejections based upon rejection in any of the multiple sequential inspections, while increasing inspection security, reduces the acceptance rate of usable gray zone containers.
Physical limitations of the inspection devices for the inspection methods, and restrictions of inspection time, result in the limited inspection of only a portion of the liquid of the container volume. Methods relying upon the direct illumination of particles by light sources, e.g. perpendicularly directed at a plane through the container axis, wide or narrow width, collimated light, i.e., light extinction illumination, such as disclosed in U.S. Pat. No. 3,900,266, usually result in only a fraction of the particles passing through the scanned light beam paths during the inspection time, depending on initial particle position velocity, and the duration of the inspection period.
Even with illumination of the entire solution, by high intensity forward scattering light (light that is oriented outside the acceptance angle of the viewing lens to illuminate the entire solution), only a small portion of the solution is inspected at any instant in time. Particle imaging methods relying on a determination of the edges of the imaged particles are limited in accuracy by the focal length at which sharpness of focussed image can be obtained. For example, for an f1.0 lens with a focal length of 75 mm, at unity, object to image size ratio (permitting full resolution of the lens), the depth of acceptable image sharpness is approximately 0.2 mm. This can be increased to approximately 1.6 mm by reducing the lens aperture to f8.0. However, even the smallest containers range in size from 10-30 millimeters in diameter. As a result, even with full container illumination, only a very shallow portion of the solution, is sufficiently in focus for accurate inspection and particle size determinations based upon this type of particle imaging. In addition, such systems are susceptible to inherent errors caused by system vibration, which tends to limit accurate focussing.
For those systems employing some version of light extinction particle detection, the use of collimated light with an on-axis column array of photo detectors define a small volume particle detection zone. Typically the zone is 1 mm wide and includes the liquid height of the container.
In both types of detection systems, the proportion of the container volume inspected for particulate contamination at any instant in time is small. There is explicit dependence upon particle motion within the container to bring the particle through the detection zone for the inspection to be effective.
In particular designs, some high brightness areas are vignetted during the inspection period to accommodate the limited dynamic range of the detector employed. In some designs the container bottom is vignetted during the inspection period and in other designs, the meniscus portion of the container is vignetted either alone or with the container bottom. In both cases, the inspected volume of the container is reduced, thus reducing the security of the inspection.
In order to increase rejection probability of required rejects, two scans, with rejection in either one, can be utilized but with reduction in rate of overall production processing and a reduction of acceptable gray zone containers. With two or three scans it is also possible to use both forward scatter lighting and direct lighting (typically with an intensity from 0.001 to 0.01 that of the forward scatter beam intensity) to illuminate particles, susceptible to each, in separately illuminated scans, such as described in U.S. Pat. No. 4,492,475. Light colored particles reflect and scatter light toward the detector with a net increase in light energy collected, i.e., positive height pulses. Dark colored particles do not reflect light well but rather block off direct lighting which, with a resultant shadow and a decrease in energy toward the detector, result in reduced signal output, i.e., negative height pulses. The use of two sequential measurements with rejection, if rejected in either respect, is however, less effective than the combined use of both types of illumination in a single station.
Despite greater effectiveness, utilization of both types of lighting in a single scan, such as for example, disclosed in U.S. Pat. No. 4,676,650, introduces algebraic errors with reduction in inspection efficiency. These errors result from illumination of particles, which are susceptible to illumination and detection by both types of lighting, i.e., positive energy imaging from forward scattering light reflections and negative energy from shadowing of direct lighting.